Intermediates for and synthesis of 3-methylene cephams

ABSTRACT

The present invention relates to novel processes for the preparation of 3-methylenecephams. More specifically, the present invention relates to the intramolecular cyclization of penicillin sulfoxide derived monocyclic azetidinone derivatives with organometallic catalysts of the formula III.wherein:M is Sc, Y, La, Ce, Pr, Nd, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, Lu, Zr, Hf, Th, Nb, Ta, U, Bi, or In;E is O[SO2(C1-C6 polyfluoroalkyl)], N[SO2(C1-C6 polyfluoroalkyl)]2, or C[SO2(C1-C6 polyfluoroalkyl)]3;x is 3;y is 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9.

This application claims the benefit of U.S. Provisional Application Ser.No. 60/183,083 filed Feb. 16, 2000 and is the national phase ofInternational Application PCT/US01/04410, filed Feb. 10, 2001.

BACKGROUND OF THE INVENTION

Since the early 1940's penicillins, and more recently cephalosporins,have been utilized in man's fight against bacterial infections. Thesetwo classes of molecules were the first effective treatments for lifethreatening infections. Over the past 50 years a tremendous effort hasbeen expended by the scientific community to develop increasinglyeffective forms of these antibiotics. This effort has led to theidentification of specific molecules of great importance to the globalmedical community. Cefaclor and cephalexin are two examples ofcephalosporin antibiotics that have been developed through this process.Despite years of continuing research on new antibiotics, manypenicillins and cephalosporins are still widely utilized in the everyday fight against pathogenic bacteria.

The primary drawbacks associated with cephalosporins relate to thedifficulty and expense of their synthetic production. Several of theseimportant compounds are derived through the synthetic transformation ofa penicillin substrate which is itself acquired through a fermentationprocess. Many steps in the conversion of penicillins to cephalosporinsare typically performed using reagents which pose a number of health andenvironmental risks. In addition, these reagents present economicdisadvantages of high outright cost as well as a high cost associatedwith disposal of the generated waste. These factors significantly affectthe overall cost of producing cephalosporin antibiotics.

The present invention relates to novel processes for the preparation of3-methylenecephams. The present invention utilizes specific catalystsand novel intermediates which have a member of advantages over theanalogous procedures known in the art. These catalysts are typicallyutilized in a less than stoichiometric amount, which may also berecovered and reused, thereby allowing for lower material costs as wellas significantly lower waste disposal costs. These two importantfeatures combine to lower the overall production cost of3-methylenecephams and some novel starting materials even eliminate theneed for catalysts at all. More specifically, the present inventionrelates in part to the intramolecular cyclization of penicillinsulfoxide derived monocyclic azetidinone derivatives either thermally orwith metal salt catalysts.

SUMMARY OF THE INVENTION

The present invention is directed to a process of preparing compounds ofthe formula I:

said process comprising the step of reacting a compound of the formulaII;

with a catalyst of the formula III in an inert solvent;

wherein:

M is Sc, Y, La, Ce, Pr, Nd, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, Lu, Zr,Hf, Th, Nb, Ta, U, Bi, or In;

E is O[SO₂(C₁-C₆ polyfluoroalkyl)], N[SO₂(C₁-C₆ polyfluoroalkyl)]₂, orC[SO₂(C₁-C₆ polyfluoroalkyl)]₃;

x is the common oxidation state of the metal M;

y is 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9;

R is a carboxylic acid protecting group;

R′ is hydrogen or a carboxylic acid protecting group;

R₁ is a group of the formula;

R₂ is C₂-C₄ alkenylene, C₂-C₄ alkylene, 1,2-phenylene, or1,2-cyclohexenylene;

R₂′ is C₁-C₃ alkyl, C₁-C₆ haloalkyl, C₁-C₃ alkoxy, or2,2,2-trichloroethoxy;

R₃ is hydrogen, C₁-C₃ alkyl, halomethyl, cyanomethyl,3-(2-chlorophenyl)-5-methylisoxazol-4-yl, benzyloxy, 4-nitrobenzyloxy,2,2,2-trichloroethoxy, tert-butoxy, 4-methoxybenzyloxy, phenyl,substituted phenyl, a group of the formula R⁰—(Q)_(m)—CH₂—, aheteroarylmethyl group of the formula R″CH₂—, or a substituted arylalkylgroup of the formula

R⁰ is phenyl, substituted phenyl, 2-thienyl, 3-thienyl, or1,4-cyclohexyldienyl;

R″ is 2-furyl, 3-furyl, 2-thiazolyl, or 5-isoxazolyl;

m is 0 or 1,

Q is O or S;

W is protected hydroxy, or protected amino;

Y is hydrogen, acetyl, or nitroso;

X is chloro, bromo, —OR₄, —SR₅, or —NR₆R₇ wherein: (a) R₆ is hydrogenand R₇ is hydrogen, phenyl, substituted phenyl, or —NHR₈; or wherein (b)R₆ is —COOR₉ or —COR₉ and R₇ is —NH—COOR₉ or —NH—COR₉; or wherein (c)R₆, R₇, and the nitrogen to which each is attached combine to form animido group of the formula

R₄ is hydrogen, C₁-C₁₀ alkyl, (C₁-C₃ alkyl)aryl, C₁-C₆ haloalkyl, or—COR₁₀;

R₅ is C₁-C₆ alkyl, phenyl, substituted phenyl, (C₁-C₃ alkyl)phenyl, or(C₁-C₃alkyl)substituted phenyl;

R₈ is aminocarbonyl, C₁-C₃ alkylaminocarbonyl, C₁-C₃ alkoxycarbonyl,C₁-C₃ alkylcarbonyl, or tosyl;

R₉ is C₁-C₆ alkyl, or phenyl;

R₁₀ is C₁-C₆ alkyl, C₁-C₆ polyfluoroalkyl, C₃-C₆ cycloalkyl, adamantyl,phenyl, substituted phenyl, (C₁-C₃ alkyl)phenyl, or (C₁-C₃alkyl)substituted phenyl, or a group of the formula

Z is solid polymer support; and

Z₁ is one or two groups independently selected from the group consistingof hydrogen, halo, hydroxy, protected hydroxy, nitro, cyano,trifluoromethyl, C₁-C₄ alkyl, and C₁-C₄ alkoxy.

The present invention is also directed towards the novel compounds ofFormula IIA below:

R is a carboxylic acid protecting group;

R₁ is a group of the formula;

R₂ is C₂-C₄ alkenylene, C₂-C₄ alkylene, 1,2-phenylene, or1,2-cyclohexenylene;

R₂′ is C₁-C₃ alkyl, C₁-C₆ haloalkyl, C₁-C₃ alkoxy, or2,2,2-trichloroethoxy;

R₃ is hydrogen, C₁-C₃ alkyl, halomethyl, cyanomethyl,3-(2-chlorophenyl)-5-methylisoxazol-4-yl, benzyloxy, 4-nitrobenzyloxy,2,2,2-trichloroethoxy, tert-butoxy, 4-methoxybenzyloxy, phenyl,substituted phenyl, a group of the formula R⁰—(Q)_(m)—CH₂—, aheteroarylmethyl group of the formula R″CH₂—, or a substituted arylalkylgroup of the formula

R⁰ is phenyl, substituted phenyl, 2-thienyl, 3-thienyl, or1,4-cyclohexyldienyl;

R″ is 2-furyl, 3-furyl, 2-thiazolyl, or 5-isoxazolyl;

m is 0 or 1,

Q is O or S;

W is protected hydroxy, or protected amino;

Y is hydrogen, acetyl, or nitroso;

R₁₀ is C₁-C₆ alkyl, C₁-C₆ polyfluoroalkyl, C₃-C₆ cycloalkyl, adamantyl,phenyl, substituted phenyl, (C₁-C₃ alkyl)phenyl, diphenylmethyl, or(C₁-C₃ alkyl)substituted phenyl, or a group of the formula

Z is solid polymer support; and

Z₁ is one or two groups independently selected from the group consistingof hydrogen, halo, hydroxy, protected hydroxy, nitro, cyano,trifluoromethyl, C₁-C₄ alkyl, and C₁-C₄ alkoxy.

The present invention is also directed towards a process of preparing acompound of Formula I, as described above, wherein said processcomprises heating a compound of the Formula IIA, as described above, toa temperature of about 40° C. to about 200° C.

DETAILED DESCRIPTION OF THE INVENTION

The term “C₁-C₁₀ alkyl” as used herein includes both straight andbranched alkyl groups; including but not limited to methyl, ethyl,propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, isopropyl,sec-butyl, tert-butyl, neopentyl, isopentyl, and the like. Includedwithin the definition of “C₁-C₁₀ alkyl” are also the groups “C₁-C₈alkyl”, “C₁-C₆ alkyl”, “C₁-C₅ alkyl”, “C₁-C₄ alkyl”, and “C₁-C₃ alkyl”.

The term “alkoxy” as used herein designates an alkyl group attachedthrough an oxygen atom. Examples include but are not intended to belimited to methoxy, ethoxy, pentoxy, and the like.

The term “C₁-C₃ alkoxycarbonyl” as used herein includes, but is notlimited to, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, andisopropoxycarbonyl.

The term “C₁-C₆ polyfluoroalkyl” as used herein includes both straightand branched alkyl groups; including but not limited to methyl, ethyl,propyl, butyl, pentyl, hexyl, which are substituted with from 2-13fluorine atoms. The number of fluorine atoms will never exceed theavailable valency of the alkyl group. For example, a methyl group couldbe substituted with 2 or 3 fluorine atoms, an ethyl group with 2-5fluorine atoms, and a propyl group with 2-7 fluorine atoms. Substitutioncan occur independently at any of the available cites.

The term “halo” as used herein includes fluoro, bromo, chloro, and iodo.

The term “protected amino” as employed herein represents amino groups inwhich the either one or both of the amine hydrogens have been exchangedwith a commonly employed protecting group. Protecting groups of thistype are well know in the art and are additionally described in: T. W.Greene, Protective Groups in Organic Synthesis, John Wiley & sons,(1981) and T. G. Greene and P. Wutz, Protective Groups in OrganicSynthesis, second ed. Preferred amino protecting groups include but arenot limited to tert-butoxycarbonyl, benzyloxycarbonyl,4-methoxybenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl,2,2,2-trichloroethoxycarbonyl, allyloxycarbonyl or the1-carbomethoxy-2-propenyl group formed with methyl acetoacetate.

The term “protected hydroxy” as used herein refers to the readilycleavable groups formed with a hydroxy group such as formyloxy,chloroacetoxy, benzyloxy, benzhydryloxy, trityloxy, 4-nitrobenzyloxy,trimethylsilyloxy, phenacyloxy, tert-butoxy, methoxymethoxy,tetrahydropyranyloxy, and the like. Other hydroxy protecting groups arewell know in the art and are additionally described in Greene.

The term “carboxylic acid protecting group” as used herein refers to thecommonly used groups employed to block or protect the carboxylic acidfunctionality while reactions involving other functional sites arecarried out. Such groups are well know in the art and are additionallydescribed in Greene. They include by way of example but are not intendedto be limited to the following: methyl, tert-butyl, benzyl,4-methoxybenzyl, allyl, C₂-C₆ alkanoyloxymethyl, 2-iodoethyl,4-nitrobenzyl, diphenylmethyl (benzhydryl), phenacyl, 4-halophenacyl,dimethylallyl, 2,2,2-trichloroethyl, and the like. Carboxylic acidprotecting group strategies have been utilized with penicillins andcephalosporins for over 50 years and it is important to note that askilled artisan in the art would appreciate which protecting groups arecommonly utilized in this well known area of chemistry.

The term 'substituted as used herein refers to a group which issubstituted with 1 or 2 substituents dependently selected from the groupconsisting of halo, hydroxy, protected hydroxy, nitro, cyano,trifluoromethyl, C₁-C₄ alkyl, C₁-C₄ alkoxy, amino, or protected amino.Examples of substituted phenyl include but are not intended to belimited to the following: 4-chlorophenyl, 2,6-dichlorophenyl,2,5-dichlorophenyl, 3,4-dichlorophenyl, 3-chlorophenyl, 4-bromophenyl,3,4-dibromophenyl, 3-chloro-4-fluorophenyl, and the like. A protectedhydroxyphenyl would include by way of example but is not limited to4-tetrahydropyranyloxyphenyl, 4-(4-nitrobenzyloxy)phenyl,2-phenacyloxyphenyl, 4-benzyloxyphenyl, 3-benzyloxyphenyl,4-tert-butoxyphenyl, 4-benzhydroxyphenyl, 4-trityloxyphenyl,4-tert-butyldimethylsilyloxyphenyl, and the like. Nitrophenyl groups are2-nitrophenyl, 3-nitrophenyl, and 4-nitrophenyl. By way of example othersubstituted groups would include benzyl, aryl, and the like.Importantly, the substituents can be independently selected so thatgroups like 4-bromo-3-methoxyphenyl, 4-trityloxy-2-nitrophenyl, and thelike are included herein.

The term “(C₁-C₃ alkyl) phenyl” as used herein refers to C₁-C₃ alkylgroup substituted with a phenyl group. Likewise any group in “( )” linksthe functional groups immediately proceeding and following that group.

In the forgoing definitions, hydroxy, amino, and carboxy protectinggroups are not exhaustively defined. The function of such groups is toprotect the reactive functional groups during the course of the reactionsequence and then be removed at some later time without disrupting theremainder of the molecule. A skilled artisan would appreciate that awide variety of protection strategies would be applicable to the presentinvention many of which are well know in the art and have beenextensively studied and published.

Imido groups represented when R₂ is C₂-C₄ alkenylene are maleimido,3-ethylmaleimido, 3,4-dimethylmaleimido, and like imido groups. Imidogroups represented when R is 1,2-cyclohexenylene or 1,2-phenylene are3,4,5,6-tetrahydrophthalimido or phthalimido (Ft) respectively.

Preferred Embodiments

Preferred compounds of the formula II or IIA for use in presentinvention include compounds wherein:

R is

a) a penicillin or cephalosporin carboxylic acid protecting group,

b) p-nitrobenzyl,

c) p-methoxybenzyl,

d) C₁-C₆ alkyl,

e) substituted C₁-C₆ alkyl,

f) phenyl,

g) substituted phenyl,

h) diphenylmethyl,

i) trichloroethyl,

j) benzyl, or

k) substituted benzyl.

R₁ is

a) a penicillin or cephalosporin amino side chain,

b) PhOCH₂CONH—(V—), PhCH₂CONH— (G—), or phthalimido (Ft-)

c) phthalimido.

R₁₀ is

a) C₁-C₆ alkyl,

b) methyl,

c) t-butyl,

d) substituted C₁-C₆ alkyl,

e) phenyl,

f) substituted phenyl,

g) dimethylphenyl

h) benzyl,

i) substituted benzyl

j) phenyl bonded to a polymer support.

X is

a) chloro

b) OR₄

c) bromo

Halo is preferably chloro or bromo.

Synthetic Methodology

The penicillin sulfoxide ester precursors to the compounds of formula IIare either know, readily available, or described herein; many of whichhave been utilized in the art for the preparation of cepham compounds.By way of example, they can be prepared from 6-acylamino and6-imidopenicillin acids by a) esterification and b) subsequentoxidation, usually with MCPBA, peracetic acid, or sodium periodate.

The starting materials used to prepare compounds of formula II are wellknown in the art and readily prepared by known processes. See forexample, S. Kukolja and S. R. Lammert, Angew. Chem., 12, 67-68 (1973);Kukolja U.S. Pat. No. 4,052,387; and Kukolja U.S. Pat. No. 4,159,266 allherein incorporated by reference.

Catalyzed Cyclization

It has been recognized in the art that other derivatives of azetidinonesulfinyl chlorides can be prepared by known methods, including sulfiteesters, thiosulfinate esters, and sulfinamides, and sulfinimides. Suchderivatives can be prepared by well-known conventional procedures formaking the analogous carboxylic acid derivatives. In addition tocyclizing the sulfinyl chlorides directly, the cyclization methodologyof the present invention is applicable and can be directed to suchcompounds.

The cyclization reaction of the present invention can be catalyzed by acatalyst of the formula III;

ME_(x)(H₂O)_(y)  (III)

wherein M is selected from the group consisting of Sc, Yb, La, Ce, Pr,Nd, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, Lu, Zr, Hf, Th, Nb, Ta, U, Bi,or In. E is O[SO₂(C₁-C₆ polyfluoroalkyl)], N[SO₂(C₁-C₆polyfluoroalkyl)]₂, or C[SO₂(C₁-C₆ polyfluoroalkyl)]₃; x is the commonoxidation state of the metal M; and y is 0, 1, 2, 3, 4, 5, 6, 7, 8, or9. A skilled artisan would appreciate that the lanthanides would beapplicable to the present invention. Preferred metals (M) include Hf,Sc, Zr, Bi, and Yb; the most preferred is Yb. E is preferably O(SO₂CF₃).E is also preferably N(SO₂CF₃)₂. Preferably x is 3, and y is 0 or 3 Themolecules of water associated with the catalyst will vary depending onthe particular metal (M) utilized and its oxidation state. Thecatalyst's level of hydration may or may not be crucial depending on thecircumstance of the reaction and is typically determined by thestability of the particular complex and is primarily based onconvenience and availability. The level of hydration is typically from0-4 moles per mole of catalyst.

The temperature at which the cyclization of the present invention isperformed is not crucial and can vary depending on the reactivity ofboth the catalyst and the particular compound of formula II which isbeing cyclized. The process is most preferably performed at roomtemperature. Alternatively, a temperature range from about 10° C. toabout 50° C. is preferred. Alternatively, the process can be performedat the reflux temperature of the solvent medium, which would typicallyrange from about 50° C. to about 200° C. Most preferably a refluxtemperature would be from about 70° C. to about 120° C. A skilledartisan would appreciate that the exact temperature of the reaction isnot crucial as long as the rate of the cyclization is sufficient toprovide a reasonable half-life of the starting material and product.Often one may choose a slightly lower reaction temperature, includingsub-ambient temperatures, to avoid detrimental side reactions that wouldlower the overall yield and purity of the product. Given specificcompounds of formula II and III temperatures as low as 0° C. may beappropriate.

Similarly, the solvent chosen for the reaction is not crucial. Thesolvent must be substantially inert to the other reactants andsufficiently effective to dissolve the reactants allowing them to react.The reaction need not, and may preferably not, be homogenous. A widevariety of polar and non-polar solvents may be utilized in the presentinvention. Choice of appropriate solvent will be determined by thecharacteristics of the particular compounds of formula II IIA and III,as well as the temperature at which one seeks to run the process.Preferred solvents include nitromethane, acetonitrile, tetrahydrofuran,ethers, alkanes, and mixtures thereof. Most preferred solvents includenitromethane, and acetonitrile, and mixtures thereof. Most preferredcompounds of Formula II are those wherein X is chloro.

Preparation of Compounds of Formula IIA

The compounds of Formula IIA can be prepared by techniques known in theart and according to the following scheme.

Protected penicillin sulphoxide is converted to the correspondingprotected sulphinyl chloride by procedures well know in the art (seeKukolja supra). The reaction is preferably performed utilizingN-chlorosuccinamide or N-chlorophthalimide in e.g. toluene,dichloroethane or carbon tetrachloride at reflux from about 20 minutesto 1 hour. The chloride can then be displaced by the metal salt of acarboxylic acid to form the compounds of formula IIA, wherein R₁₀ ispreferably derived from a hindered carboxylate salt. Preferred saltsinclude sodium, potassium, and silver but a skilled artisan wouldappreciate that a wide variety of salts would function in thistransformation. In addition, a wide variety of carboxylic acids wouldreact to provide compounds of Formula IIA. Most preferably the salts arepurified and dried shortly before use, or may be alternatively be fusedbefore use and the reaction performed with sonication. The reaction timeis typically from about 1-48 hours, most preferably about 24 hours. Thereaction is typically performed at room temperature but may be performeda temperatures ranging from −78° C. to the reflux temperature of thesolvent. As stated above, the choice of solvent is not critical and maybe determined by cost or convenience. Preferred solvents include tolueneand THF and preferably the reaction solvent is approximately a 2:1-1:1mixture of toluene and THF. In addition, the reaction is preferablyperformed in the dark with dry solvents to minimize undesired sidereactions.

Thermal Cyclization

The inventors have surprisingly discovered that compounds of Formula IIAcyclize to compounds of Formula I under thermal conditions. This type ofthermal cyclization is unprecedented in the literature and hastremendous advantages over methods currently practiced in the art whichrequire expensive catalysts that are cumbersome to utilize and a problemto dispose of safely.

The thermal cyclization occurs by heating a compound of Formula IIA to atemperature of from about 40° C. to about 200° C. The reaction can beperformed neat or in the presence of a solvent. The reaction ispreferably performed neat under vacuum. Conducting the reaction undervacuum has the advantage that the succinimide produced in the synthesisthe compounds of Formula IIA sublimes from the reaction mixture. Thepreferred reaction temperature is about 55° C. The preferred reactiontime is from about 0.5 hours to about 24 hours. The skilled artisan willappreciate that the rate of the reaction and production of side productswill vary depending on the temperature and duration of the reaction.Preferred temperatures and duration of reaction will vary depending onthe particular substrate of Formula IIA.

Transformation to Cephalosporin Antibiotics

The product 3-methylenecephems sulfoxides of the process of thisinvention are useful intermediates in the preparation of cephalosporinantibiotics.

The sulfoxides of Formula I can be reduced by known procedures,typically with phosphorous trichloride or phosphorous tribromide indimethylformamide, to provide the corresponding 3-methylenecephems whichare predictably converted to desacetoxycephalosporins of Formula IV,upon treatment with triethylamine in dimethylacetamide. [Chauvette andPennington, J. Org. Chem., 38, 2994 (1973)]. The desacetoxycephalosporinesters are converted to active antibiotics of Formula V, by cleaving theester function. Deprotection of the acid functionality is well known inthe art and the procedures will vary depending on the specificprotecting group.

Alternatively the exomethylenecephams can be employed in the preparationof other cephem antibiotics of the formula VI;

Wherein A may be but is not limited to chloro, bromo, methoxy, triflyl,triflyloxy, mesyl, tosyl, hydrogen, thioether, alkyl, alkenyl, or aryl.

Such chemical conversions, as well as too many others to mention, havebeen disclosed in the art and are well known. [see e.g. Chauvette andPennington, JACS., 96, 4986 (1974).] For a review of 3-chlorocephem andother 3 derivatives see, The Chemistry and Biology of BetalactamAntibiotics, vol. 1, edited by, Morin and Gorman, Academic Press, 1982Chapter 2, p 93. (See also; Tetrahedron Letters, 6043, 1988.Heterocycles, 23, 1901, 1985. J. Organic Chemistry, 54, 4962, 1989. J.Organic Chemistry, 54, 5828, 1989. Tetrahedron Letters, 3389, 1990.Synthetic Communications 20, 2185, 1990. Tetrahedron Letters, 4073,1991. J. Organic Chemistry, 58, 2296, 1993. Tetrahedron Letters. 7229,1993. J. Antibiotics, 47, 453, 1994. J. Antibiotics, 44, 498, 1991. HelvChim Acta, 60, 1510, 1977.)

In general, the exomethylenecephem compounds maybe converted by lowtemperature ozonolysis, to 3-hydroxycephems or the 3-keto equivalentswhich are in turn treated with diazomethane at room temperature toafford the 3-methoxycephem derivatives. The 3-halocephems are derivedfrom the 3-hydroxycephem esters by treatment with a halogenating agentsuch as thionyl chloride, phosphorous trichloride, or phosphoroustribromide by methods known in the art. The corresponding deprotectedcephem acids exhibit antibacterial activity. The 3-hydroxy group canalso be converted into the triflyloxy compound which can then beconverted into many different 3-carbon substituted cephems or manydifferent thio substituted cephems.

PREPARATIONS AND EXAMPLES

The following Examples are intended to demonstrate the effectiveness ofthe present invention. They are not intended to specifically define thevariety of conditions under which the present invention can be performedor limit the scope of the claims in any way. A skilled artisan willappreciate, and Applicants assert, that numerous individual alterationsof the conditions described herein will also yield effective results.

General:

All reactions were conducted, but need not be, under a dry inertatmosphere (argon or nitrogen). All glassware was dried before use in anoven (ca. 150° C.) or flame dried under argon and cooled under a dryinert atmosphere. Solvents and reagents were purified and dried asdescribed by Perrin and Armarego; CCl₄ was distilled from P₂O₅ andstored over 4 Å molecular sieves under a dry inert atmosphere. (3R, 5R,6R)-Methyl 6-phthalimidopenicillanate sulphoxide was dried over P₂O₅ invacuo for 48 h and then stored in a desiccator containing selfindicating silica gel. (2R)-Methyl 2-[(2R,3R)-2-acetoxysulphinyl-4-oxo-3-phthalimido-1-azetidinyl]-3-methyl-3-butenoatewas stored temporarily in a desiccator containing self indicating silicagel. N-Chlorosuccinimide was crystallised from AcOH, washed with AcOHthen hexane and dried in vacuo for 48 h and stored at 4° C. in the dark.NaOAc is hygroscopic and was used directly from a fresh bottle, or wasfused in situ under vacuum (ca. 0.1 mmHg). ESI mass spectra wererecorded in the positive ion mode.

For determination of the yields in the conversion of (2R)-methyl 2-[(2R,3R)-2-acetoxysulphinyl-4-oxo-3-phthalimido-1-azetidinyl]-3-methyl-3-butenoateto methyl 3-methylene-7-phthalimidocepham-4-carboxylate 1-oxide theinternal standard method was used. A reference mixture of methyl3-methylene-7-phthalimidocephamrcarboxylate 1-oxide and the internalstandard tri-tert-butylbenzene was prepared for calibration. Theinternal standard produced a peak with an disproportionately greaterarea than that for the azetidinone peaks. After drying the productmixtures in vacuo, 1 equivalent of tri-tert-butylbenzene was added. Themixtures were then dissolved in CDCl₃ and analyzed by ¹H NMRspectroscopy. The integral was measured from 1.2 to 1.5 ppm for thetrimethyl signal (1.34 in CDCl₃) of the internal standard and wascompared to those of both azetidinone signals (5.95 and 4.90) summedtogether for the (R)-diastereoisomer of methyl3-methylene-7-phthalimidocepham-4-carboxylate 1-oxide. In mixtures wherethe (S)-diastereoisomer of methyl3-methylene-7-phthalimidocepham-4-carboxylate 1-oxide was visible thesepeaks were also measure (5.62 and 4.91).

Example 1

(2R)-Methyl 2-[(2R,3R)-2-acetoxysulphinyl-4-oxo-3-phthalimido-1-azetidinyl]-3-methyl-3-butenoate.(R₁=Ft, R=methyl, and R₁₀=methyl)

i) Using AgOAc:

A solution of (3R, 5R, 6R)-methyl 6-phthalimidopenicillanate sulphoxide(250 mg, 0.66 mmol) and N-chlorosuccinimide (89 mg, 0.66 mmol) in CCl₄(14 mL) was stirred under reflux under an atmosphere of argon for 70min. Once the solution had cooled AgOAc (110 mg, 0.66 mmol) was addedand the mixture was stirred under reflux for a further 40 min. Theproduct mixture was diluted with CHCl₃ (20 mL), the solids allowed tosettle and filtered whilst hot using a heated metal cannula fitted witha filter paper filter into another vessel. The remaining silver saltswere washed with CHCl₃ (10 mL) and the filtration procedure wasrepeated. The combined CHCl₃ portions were washed with distilled water(5 mL) and saturated aqueous solution of NaCl (10 mL), dried (MgSO₄) andevaporated to give a white foam (295 mg). It is not necessary to washthe product with water, however, this removes succinimide produced inthe reaction. The ¹H NMR spectrum of the crude product revealed that itwas composed of the title compound (82% of the mixture as a 1:1 mixtureof diastereoisomers, epimeric at sulphur), (2R)-methyl 2-[(2R,3R)-2-chloro-4-oxo-3-phthalimido-1-azetidinyl]-3-methyl-3-butenoate (4%of the mixture), (2R)-methyl 2-[(2R,3S)-2-acetoxy-4-oxo-3-phthalimido-1-azetidinyl]-3-methyl-3-butenoate (3%of the mixture), methyl3-methylene-7-phthalimidocepham-4-carboxylate-1-oxide (10% of themixture) and putative (2R)-methyl 3-methyl-2-[(2R,3S)-2-succinimidyl-4-oxo-3-phthalimido-1-azetidinyl]-3-butenoate (0.6%of the mixture). Only the NMR signals for the title compound arereported ¹H NMR (CDCl₃, 300 MHz) 1.91 (s, 3H, OAc), 2.00 (s, 3H, CH₃),2.03 (s, 3H, CH₃), 2.12 (s, 3H, OAc), 383 (s, 3H, CO₂CH ₃), 3.85 (s, 3H,CO₂CH₃), 4.98 (s, 1H), 5.07 (s, 1H), 5.08 (s, 1H), 5.18 (s, 1H), 5.24(d, J=1.3 Hz, 1H), 5.39 (d, J=5.3 Hz, 1H, azetidinyl-H), 5.42 (s, J=5.0Hz, 1H, azetidinyl-H), 5.76 (d, J=5.0 Hz, 1H, azetidinyl-H), 5.83 (d,J=5.3 Hz, 1H, azetidinyl-H), 7.78 (m, phthalimido), 7.88 (m,phthalimido); ¹³C NMR (CDCl₃) 20.3, 20.8, 21.0, 21.1, 52.6, 52.7, 55.8,56.5, 58.9, 60.5, 75.3, 79.2, 116.9, 118.7, 123.9, 131.0, 131.5, 134.6,135.0, 137.3, 138.9, 163.6, 163.8, 166.3, 166.5, 167.5, 167.8, 168.5,168.6; CIMS m/z 394 [93%, (M-58)NH4], 377 [34, (M-58)H+], 376 (94,M-58), 359 (48), 346 (51), 329 (35), 297 (21), 190 (20), 189 (20), 172(30), 130 (100), 124 (47), 112 (91), 80 (15), 59 (24); ESIMS (MeCN) m/z473 (40%, MK+), 457 (100, MNa+), 435 (60, MH+); ESIMS (MeCN, CsI) 567(100%, MCs+); IR (thin film, KBr) 1792 (m), 1778 (m), 1725 (s), 1387(m), 1190 (w), 1164 (w), 1138 (w), 718 (w).

ii) Using NaOAc:

A solution of (3R, 5R, 6R)-methyl 6-phthalimidopenicillanate sulphoxide(25 mg, 0.07 mmol) and N-chlorosuccinimide (9 mg, 0.07 mmol) in CCl₄(1.4 mL) was stirred under reflux under an atmosphere of argon for 70min. To the product was added NaOAc (6 mg, 0.07 mmol) and theheterogeneous mixture was stirred under reflux for 1 h. The mixture wasdiluted with CHCl₃ (3.5 mL), dried (MgSO₄), filtered and evaporated togive a transparent oil (32 mg). The ¹H NMR spectrum of the crude productrevealed that it was composed of the title compound (64% of the mixtureas a 1:1 mixture of diastereoisomers, epimeric at sulphur), (2R)-methyl2-[(2R,3R)-2-chloro-4-oxo-3-phthalimido-1-azetidinyl]-3-methyl-3-butenoate (17%of the mixture), (2R)-methyl 2-[(2R,3S)-2-acetoxy-4-oxo-3-phthalimido-1-azetidinyl]-3-methyl-3-butenoate(15% of the mixture), putative (2R)-methyl 3-methyl-2-[(2R,3S)-2-succinimidyl-4-oxo-3-phthalimido-1-azetidinyl]-3-butenoate (4% ofthe mixture) and succinimide. The succinimide can be removed by anaqueous wash.

The following examples were prepared substantially in accordance withthe procedure above with the variations noted below. The products werenot isolated but rather were characterized by NMR using known resonancesof the azetidinone protons and were reacted directly to prepare compoundof Formula I. Ft=phthalimido, PNB=p-nitrobenzyl, V=phenoxyacetyl

Ex.# R₁ R R₁₀Salt Time/T/sol. 1a Ft Methyl AcONa 1h/reflux/CCl₄ 1b FtMethyl AcOAg 40 min/reflux/CCl₄ 1c Ft Methyl BzOAg 40 min/reflux/CCl₄ 1dV PNB AcOAg 18h/RT/Tol 1e V PNB AcONa 18h/RT/Tol-THF 1e V PNB AcOK18h/RT/Tol 1f V PNB BzOAg 15.5h/RT/Tol 1g V PNB BzOK 21h/RT/Tol-THF 1h VPNB 1-adamantyl 25h/RT/THF/ —CO₂Na 1I V PNB Me₃CCO₂Na 18h/RT/Tol-Ether

Example 2

(4R, 6R, 7R)-Methyl 3-methylene-7-phthalimidocepham4-carboxylate-1-oxide (R₁=Ft, R=methyl, and R₁₀=methyl)

i) Ytterbium(III) triflate-catalysed cyclization of sulphinyl acetatesin MeNO₂:

To (2R)-methyl 2-[(2R,3R)-2-acetoxysulphinyl-4-oxo-3-phthalimido-1-azetidinyl]-3-methyl-3-butenoate(15 mg, ca. 0.035 mmol since not pure) in MeNO₂ (500 L) was added[Yb(OH₂)₉](OTf)₃ (2.7 mg, 0.004 mmol). The mixture was stirred at roomtemperature for 3 (run 1) and 5 h (run 2). The mixtures were dilutedwith CHCl₃ (1.5 mL) and washed with a saturated aqueous solution of NaCl(0.2 mL). The aqueous wash was extracted with CHCl₃ (0.5 mL). Thecombined CHCl₃ was dried MgSO₄), filtered and evaporated to provide thetitle product (run 1: 11 mg; run 2: 12 mg). To the dried products wasadded tri-tert-butylbenzene (8.6 mg in each, 0.035 mmol). The mixtureswere dissolved in CDCl₃ and analysed by ¹H NMR spectroscopy. Because oneof the (S)-diastereoisomer signals (5.62) was obscured by otherresonances and therefore not measurable, the integral totals for thesignals at ca. 4.9 [(R)- and (S)-diastereoisomers present as overlappingdoublets) were doubled to estimate the total for both diastereoisomers.These values were scaled with reference to the internal standard anddivided by the total measured for the (R)-diastereoisomer of titlecompound in a reference run [13 mg, 0.035 mmol and tri-tert-butylbenzene(8.6 mg, 0.035 mmol) in CD₃NO₂ (500 L)] indicating yields of 65 (run 1)and 73% (run 2).

ii) Ytterbium(III) triflate-catalysed cyclisation of sulphinyl acetatesin MeNO₂:

To (2R)-methyl 2-[(2R,3R)-2-acetoxysulphinyl-4-oxo-3-phthalimido-1-azetidinyl]-3-methyl-3-butenoate(60 mg, ca. 0.14 mmol since not pure) in MeNO₂ (2 mL) was added[Yb(OH₂)₉](OTf)₃ (11 mg, 0.014 mmol). The mixture was stirred for 5 h atroom temperature and was then diluted with CHCl₃ (6 mL) and washed witha saturated aqueous solution of NaCl (0.8 mL). The aqueous portion wasextracted twice with CHCl₃ (2 mL then 1 mL). The combined CHCl₃ wasdried MgSO₄), filtered and evaporated to provide a yellow gum (56 mg).This was purified by radial chromatography (1 mm plate of SiO₂; 10%EtOAc in methylene chloride with a 10% EtOAc gradient per 15 mL) givingtwo fractions [(R)- then the (S)-diastereoisomer of the title compound,total 27 mg, 0.072 mmol, 51% in a 4.4:1.0 ratio).

The following examples were prepared substantially in accordance withthe procedure above with the variations noted below. The yield expressedis either crude or isolated and includes all isomeric forms of thedesired product. The products were characterized by NMR using the knownresonances of the azetidinone protons. These resonances are well knownand very distinctive.

Ex.# R₁ R R₁₀ Time/T/sol. Catalyst Yield 2a Ft Methyl Methyl 3h/RT/MeNO₂[Yb(OH₂)₃](OTf)₃ 65% 2b Ft Methyl Methyl 5h/RT/MeNO₂ [Yb(OH₂)₃](OTf)₃73% 2c Ft Methyl Methyl 6d/RT/MeAc Yb(OTf)₃ 10% 2d Ft Methyl Methyl7.5h/RT/EtNO₂ [Yb(OH₂)₃](OTf)₃ 40% 2e Ft Methyl Methyl 7.5h/RT/AcOR[Yb(OH₂)₃](OTf)₃ 20% 2f Ft Methyl Methyl 68h/RT/MeCN Yb(OTf)₃ >10%  2gFt Methyl Methyl 68h/RT/CH₂Cl₂ Yb(OTf)₃ >10%  2h Ft Methyl Methyl68h/RT/THF Yb(OTf)₃ >10%  2I Ft Methyl Phenyl 3h/RT/MeNO₂[Yb(OH₂)₃](OTf)₃ 50% 2j V PNB CMe₃ 23h/RT/MeNO₂ Yb(OTf)₃ 56% 2k V PNB 1-45h/RT/MeNO₂ Yb(OTt)₃ 24% adamantyl NMR of product from 2j ¹H NMR(CDCl₃,270 MHz) δ 3.2(1H, d, H2a), 3.62(1H, d, H2b), 4.54(2H, s, PhOCH₂),5.21(1H, s), 5.27(2H, s, CO₂CH₂), 5.29(1H, s), 5.31(1H, s), 5.43(1H,d,), 5.76(1H, dd,), 7.9(2H, d, Ph), 7.0(1H, t, Ph), 7.32(2H, t, Ph),7.49(2H, d, ArNO₂), 8.25(2H, d, ArNO₂).

Example 3

The following examples were prepared as noted below. The yield expressedis either crude or isolated and includes all isomeric forms of thedesired product. The products were characterized by NMR using the knownresonances of the azetidinone protons and as described in Example 3.

Ex.# R₁ R R₁₀ Time/T/sol. Yield 3a V PNB Methyl 4h/reflux/Tol 26% 3b VPNB Methyl 0.5h/125°/neat 28% 3c V PNB Methyl 13h/55°/neat 50% 3d V PNBPhenyl 0.5h/125°/neat 22% 3e V PNB CMe₃ 1h/100°/neat 18% 3f V PNB CMe₃4.5h/reflux/Tol 17% 3g V PNB CMe₃ 19h/65°/neat 29% 3h V PNB Benzyl.5h/125°/neat 31%

Example 4

The following sulphinyl chloride derivative of Formula IIB was reactedunder conditions illustrated below and as described in Example 2, toprovide products of Formula I.

Ex.# R₁ R Catalyst Time/T/sol. Yield 4a V PNB Yb(OTf)₃ 40h/rt/MeNO₂ ¹53%  4b V PNB Yb(OTf)₃ 38h/rt/MeNO₂ ¹ 64%² 4c V PNB [Yb(OH₂)₃](OTf)₃120h/rt/MeNO₂ ¹ 12%² 4d V PNB Yb(OTf)₃ 21h/rt/MeNO₂ 46%² 4e V PNBYb(OTf)₃ 22h/rt/MeNO₂ 30%² 4f V PNB Yb(OTf)₃ 22h/rt/MeNO₂ 72%² 4g V PNBYb(OTf)₃ 22h/rt/MeNO₂ 57%² ¹1 eq. Sodium t-butyl acetate added ²Yielddetermined by NMR and as described in Example 2.

We claim:
 1. A process of preparing compounds of the formula I:

said process comprising the step of reacting a compound of the formulaII;

ME_(x)(H₂O)_(y)  (III) with a catalyst of the formula III in an inertsolvent; wherein: M is Sc, Y, La, Ce, Pr, Nd, Sm, Eu, Gd, Tb, Dy, Ho,Er, Tm, Yb, Lu, Zr, Hf, Th, Nb, Ta, U, Bi, or In; E is O[SO₂(C₁-C₆polyfluoroalkyl)], N[SO₂(C₁-C₆ polyfluoroalkyl)]₂, or C[SO₂(C₁-C₆polyfluoroalkyl)]₃; x is 3 or when M is Th then x is 4; y is 0, 1, 2, 3,4, 5, 6, 7, 8, or 9; R is a carboxylic acid protecting group; R′ ishydrogen or a carboxylic acid protecting group; R₁ is a group of theformula;

R₂ is C₂-C₄ alkenylene, C₂-C₄ alkylene, 1,2-phenylene, or1,2-cyclohexenylene; R₂′ is C₁-C₃ alkyl, C₁-C₆ haloalkyl, C₁-C₃ alkoxy,or 2,2,2-trichloroethoxy; R₃ is hydrogen, C₁-C₃ alkyl, halomethyl,cyanomethyl, 3-(2-chlorophenyl)-5-methylisoxazol-4-yl, benzyloxy,4-nitrobenzyloxy, 2,2,2-trichloroethoxy, tert-butoxy,4-methoxybenzyloxy, phenyl, substituted phenyl, a group of the formulaR⁰—(Q)_(m)—CH₂—, a heteroarylmethyl group of the formula R″CH₂—, or agroup of the formula

R⁰ is phenyl, substituted phenyl, 2-thienyl, 3-thienyl, or1,4-cyclohexyldienyl; R″ is 2-furyl, 3-furyl, 2-thiazolyl, or5-isoxazolyl; m is 0 or 1, Q is O or S; W is protected hydroxy, orprotected amino; Y is hydrogen, acetyl, or nitroso; X is chloro, bromo,—OR₄, —SR₅, or —NR₆R₇ wherein: (a) R₆ is hydrogen and R₇ is hydrogen,phenyl, substituted phenyl, or —NHR₈; or wherein (b) R₆ is —COOR₉ or—COR₉ and R₇ is —NH—COOR₉ or —NH—COR₉; or wherein (c) R₆, R₇, and thenitrogen to which each is attached combine to form an imido group of theformula

R₄ is hydrogen, C₁-C₁₀ alkyl, (C₁-C₃ alkyl)aryl, C₁-C₆ haloalkyl, or—COR₁₀; R₅ is C₁-C₆ alkyl, phenyl, substituted phenyl, phenyl(C₁-C₃alkyl), or substituted phenyl(C₁-C₃ alkyl); R₈ is aminocarbonyl, C₁-C₃alkylaminocarbonyl, C₁-C₃ alkoxycarbonyl, C₁-C₃ alkylcarbonyl, or tosyl;R₉ is C₁-C₆ alkyl, or phenyl; R₁₀ is C₁-C₆ alkyl, C₁-C₆ polyfluoroalkyl,C₃-C₆ cycloalkyl, adamantyl, phenyl, substituted phenyl, (C₁-C₃alkyl)phenyl, or substituted phenyl(C₁-C₃ alkyl), or a group of theformula

Z is solid polymer support; and Z₁ is one or two groups independentlyselected from the group consisting of hydrogen, halo, hydroxy, protectedhydroxy, nitro, cyano, trifluoromethyl, C₁-C₄ alkyl, and C₁-C₄ alkoxy.2. The process of claim 1 wherein: X is chloro, bromo, or OR₄.
 3. Theprocess of claim 2 wherein: X is OR₄ and R₄ is methyl, benzyl, ort-butyl.
 4. The process of claim 1 wherein: R₁ is a group of the formula


5. The process of claim 1 wherein: R₁ is a group of the formula


6. The process of claim 4 wherein: R₁ is a phthalimido,phenoxyacctylamino, or phenylacctylamino.
 7. The process of claim 6wherein: R₁ is a phthalimido.
 8. The process of claim 6 wherein: R isC₁-C₆ alkyl, phenyl, benzyl, p-nitrobenzyl, p-methoxybenzyl,diphenylmethyl, or trichloroethyl.
 9. The process of claim 8 wherein: Ris methyl, p-nitrobenzyl, diphenylmethyl, or trichloroethyl.
 10. Theprocess of claim 4 wherein: R is methyl, p-nitrobenzyl, diphenylmethyl,or trichloroethyl; and X is chloro, bromo, or OR₄.
 11. The process ofclaim 10 wherein: R₁ is phenoxyacetylamino; R is p-nitrobenzyl; and X ischloro.
 12. The process of claim 1 wherein the reaction temperature isfrom about 20° C. to about 70° C.
 13. The process of claim 10 whereinthe reaction temperature is from about 20° C. to about 70° C.
 14. Theprocess of claim 10 wherein the reaction solvent is nitromethane,acetonitrile, or a mixture thereof.
 15. The process of claim 1 wherein Mis Hf, or Yb.
 16. The process of claim 10 wherein M is Hf or Yb; and isO(SO₂CF₃).
 17. The process of claim 1 wherein M is Yb, E is O(SO₂CF₃),and y is 0 or
 3. 18. The process of claim 10 wherein M is Yb, E isO(SO₂CF₃), and y is 0 or
 3. 19. The process of claim 1 furthercomprising the step of converting a compound of Formula I to a compoundof Formula (VI)

wherein A is chloro, bromo, hydroxy, methoxy, triflyl, mesyl, tosyl,hydrogen, C₁-C₄ alkyl, or C₁-C₄ alkenyl.
 20. The process of claim 10further comprising the step of converting a compound of Formula I to acompound of Formula (VI)

wherein A is chloro, bromo, hydroxy, methoxy, triflyl, mesyl, tosyl,hydrogen, C₁-C₄ alkyl, C₁-C₄ alkenyl.